The overall goal of this project is to identify genes that are involved in the development of airflow obstruction and airway inflammation in asthmatics, and to determine whether polymorphisms in these differentially expressed genes predispose individuals to develop asthma. Asthma is a complex genetic disorder that is caused by a number of unique gene-gene and gene-environment interactions. The search for asthma susceptibility genes has been complicated by the broad clinical phenotype of asthma, the polygenic inheritance pattern of this disease, and the substantial role of environmental exposures in the development and progression of asthma. Inhaled environmental agents induce several very specific biologic responses in asthmatics; including the induction of acquired and innate immunity that leads to acute and chronic forms of airway inflammation and airway remodeling. Emerging evidence indicates that both acquired and innate immune responses in the lung may be influenced by polymorphic genes. For instance, functional polymorphisms in the IL-4 receptor gene are thought to preferentially stimulate acquired Th2 immune responses to inhaled allergens, and we have recently shown that common co-segregating mutations in TLR4 (a transmembrane receptor for LPS) are associated with diminished airway responsiveness to inhaled LPS. In this project, we hypothesize that polymorphisms of genes expressed by airway cells in asthmatics following specific subsegmental airway challenges predispose individuals to the development of asthma. To test this hypothesis, we plan to use the following aims to identify the genes that are differentially expressed by cells in the airway epithelia following specific subsegmental airway challenge with stimuli that induce acquired (house dust mite) or innate (LPS) immune responses, and then determine whether polymorphisms in these genes are associated with the development of asthma in a separate, well characterized, familial cohort of asthmatics. 1. Cells from the airway epithelia will be obtained from 4 study populations (atopic asthmatics, non-atopic asthmatics, atopic non-asthmatics, and non-atopic non-asthmatics) following specific subsegmental airway challenge with saline, house dust mite allergen, and LPS. 2. Candidate asthma susceptibility genes will be identified by measuring levels of gene expression and determining which genes are associated with the airway response to either house dust mite or LPS in asthmatics. 3. Intragenic polymorphic markers or markers linked to candidate genes will be identified. 4. A linkage and association study will be performed in a previously characterized familial cohort of asthmatics using selected candidate genes/loci identified in the previous aims. 5. Candidate genes shown to be associated with asthma will be analyzed for sequence polymorphisms in asthmatics.